Neurodevelopmental models of the pathology of schizophrenia propose that individuals with schizophrenia inherit genes that cause structural brain deviations; these deviations may be compounded by environmental insults. Seven studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis and adult psychosis have reported that cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. Clinical studies indicate that illicit substance use, particularly cannabis use, occurs commonly in adolescents with schizophrenia and is associated with increased symptom severity. These data suggest that research is needed to understand the mechanisms underlying the association between cannabis use and psychosis. To date, little is known about the impact of recurrent exposure to cannabis on brain anatomy in either healthy adolescents or adolescents with schizophrenia. There is increasing evidence that schizophrenia has a white matter component. Cannabinoid CB1 receptors are abundant in white matter areas during postnatal brain development and there is ongoing development of white matter, especially in the frontal lobes, during adolescence. In this application, we propose to conduct a longitudinal study to examine the association between repeated exposure to cannabis and white matter abnormalities in the superior frontal gyrus region in healthy adolescents and adolescents with schizophrenia using both diffusion tensor imaging (DTI) and volumetric analysis. Preliminary DTI data from our group indicate that cannabis use is associated with reduced frontal white matter integrity (as measured by lower fractional anisotropy levels using DTI) in healthy adolescents. Second, in adolescents with schizophrenia, comorbidity of cannabis misuse was associated with greater deficits in frontal white matter integrity than what was observed in schizophrenia or cannabis use alone. In adolescents with schizophrenia, decreased fractional anisotropy levels were significantly correlated with attentional impairments, a core neurocognitive deficit associated with schizophrenia. Further studies are now needed to confirm these initial findings. The specific aims of this proposal are to: 1) examine the impact of repeated exposure to cannabis in adolescents with schizophrenia and healthy controls on fractional anisotropy levels (FA) and volume of brain white matter in the superior frontal gyrus region and 2) correlate findings from DTI studies with neurocognitive functions, clinical symptoms and quantitative structural MRI abnormalities to understand the correlates of abnormal fractional anisotropy. A positive finding would help inform current neurodevelopmental models of schizophrenia and point to an intervention that might prevent worsening of the illness. [unreadable] [unreadable] [unreadable]